Autism is defined as a single disorder characterized by impairments in communication and social interaction and the presence of restricted interests and repetitive behaviors. The current diagnostic definition is based on behavioral characteristics, but there is mounting evidence that autism may represent a collection of overlapping neurodevelopmental disorders, resulting from a variety of neuroanatomical, neurophysiological, neuroimmunologic and/or genetic abnormalities. The wide range of possible etiologies and the heterogeneity of symptom expression among individuals with autism leads to speculation that there actually are several "autisms", i.e., clinically meaningful subtypes of the disorder that may have distinct causes, symptoms, comorbid conditions and treatments. The PDN research program aims to characterize the behavioral and biological manifestations of these subtypes of autism, and to examine the connection between the two, in an effort to identify unique etiologies and to develop more effective therapeutic and preventive interventions. During the reporting period, this project focused primarily on a longitudinal, phenotyping investigation of young children (ages 1-6 years) with autism. In addition, two new studies were implemented with initial recruitment. The goal of the first is stated in its title: "Identification of Characteristics Associated with Symptom Remission in Autism". This investigation is comparing children who were previously diagnosed with autism, whose symptoms have remitted (partially or completed), with a cohort of similarly aged children who received similar interventions (behavioral, pharmacological and biomedical) but did not significantly improve. It is hoped that specific predictors of response can be identified in the remitted group, which will lead to the development and application of more effective treatmens for the larger cohort of individuals with autism spectrum disorders. The study is actively recruiting children and adolescents with a history of remitted autism and their age-/sex-matched contrast groups. More information about the remitted autism study can be found at: http://clinicaltrials.gov/ct2/show/NCT00938054. The second recently approved study is just beginning to recruit subjects for piloting, which will permit the use of oxytocin and vasopressin as probes in a functional neuroimaging study of social cognition among young adults with autism spectrum disorders and age-/sex-matched healthy volunteers. This investigation utilizes functional magnetic resonance imaging (fMRI) to assess the impact of double-blind single administration of oxytocin, vasopressin or placebo on behavior and brain function in response to tasks of social cognition. Comparisons across groups, tasks and drugs will be made to determine if individuals with autism have different patterns of brain activation compared to normal controls, as well as pre and post dose of neuropeptide or placebo, per the experimental design. The investigation will provide greater understanding of the nature of autism's social deficits and the activation patterns may provide important clues into the pathophysiology of the disorder, which in turn could lead to the development of novel therapeutic strategies. More information about the fMRI study can be found at http://www.clinicaltrials.gov/ct2/show/NCT01093768?term=autism+oxytocin&rank=3. During the reporting period, recruitment continued with the study hitting the mark of enrolling over 100 children with autism. In addition, PDN staff continue to screen children for this natural history study, our enrollment continues to include less than 50 (N=45) individuals with autism and a history of regression. With 100 subjects, we are conducting initial analyses of several of our primary hypotheses, including whether or not there are significant immunological or other differences between children with autism with a history of regression and those without (with developmental regression defined by a significant loss of social and/or communication skills). In addition, we are analyzing the sample of children with autism compared to over 50 typically developing healthy volunteers and 25 children with developmental delays but no significant symptoms of autism. The baseline data we are analyzing include comprehensive behavioral, neuropsychological, medical and neurological evaluations, as well as a routine and overnight electroencephalogram (EEG), neuroimaging with magnetic resonance imaging, modified polysomnography to evaluate sleep architecture, blood and urine samples (and children with autism receive a lumbar puncture to obtain cerebrospinal fluid for analysis), as well as assessments of environmental exposures, early medical history, genetics, genomics, and dysmorphology. Preliminary results from these evaluations have demonstrated genetic abnormalities in a small fraction of the children with autism, while more than half of the children have abnormalities of sleep architecture and/or the presence of abnormal, epileptiform discharges on routine and overnight EEG tracings. The latter findings led to the development of two targeted treatment trials - use of valproic acid to treat epileptiform discharges (recently approved) and use of donepezil to improve Rapid Eye Movement (REM) sleep (closed for recruitment with data analyses underway);described in detail in Project MH002914-02: "Treatment of Medical Conditions among Individuals with Autism Spectrum Disorders" and at http://clinicaltrials.gov/ct2/show/NCT00695136 All children in the phenotyping study are being followed in the NIMH clinic for three years and will have annual evaluations that include behavioral assessments, clinical exams and laboratory studies. At the end of study participation, the comprehensive baseline evaluation will be repeated, including the laboratory assays, EEG, sleep study and MRI scans. Particular attention is being paid to the "N of 1 or 2" findings - unique physical, behavioral, genetic, neuroimaging or biochemical characteristics of children with autism that might provide clues to etiology or pathogenesis. The goal of the investigation is to determine if there are distinct groups of individuals within the spectrum of autistic disorders that share common profiles of biological and/or behavioral characteristics. Identification of such subgroups will provide new avenues for clinical and basic science research into the causes and treatments of autism. Interested parties are invited to learn more about the study at: http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html